LB0002 BARICITINIB IN JUVENILE IDIOPATHIC ARTHRITIS: A PHASE 3, DOUBLE-BLIND, PLACEBO-CONTROLLED, WITHDRAWAL, EFFICACY AND SAFETY STUDY
Authors: A. Ramanan, P. Quartier, N. Okamoto, G. Meszaros, J. Araujo, Z. Wang, R. Liao, B. Crowe, X. Zhang, R. Decker, S. Keller, H. Brunner, N. Ruperto
Journal: Annals of the Rheumatic Diseases (2022)

Background Baricitinib is a JAK1/2 selective inhibitor approved for the treatment of rheumatoid arthritis. Juvenile idiopathic arthritis (JIA) is a group of diseases characterized by immune mediated chronic arthritis which often requires treatment with conventional synthetic or biologic disease-modifying antirheumatic drugs (cs or b-DMARDs). Objectives To investigate baricitinib efficacy and safety in pediatric patients with JIA and an inadequate response to cs or b-DMARDs. Methods This Phase 3 multicenter, double-blind, withdrawal, efficacy, and safety study, enrolled patients (pts) age 2 to &lt;18 years with extended oligo- or poly-articular JIA, ERA, or JPsA, per ILAR criteria, and an inadequate response to ≥1 cs and/or b-DMARDs ( NCT03773978 ). There were 3 periods: a 2-week (wk) pharmacokinetic/safety assessment (PKS), a 12-wk open-label lead-in (OLLI), and an up-to 32-wk double-blind withdrawal (DBW). Dosage and safety were confirmed in the PKS and then pts, including those from the PKS, enrolled in the OLLI, receiving age-based, oral, once daily doses of baricitinib. Pts with a JIA-ACR30 response at wk12, end of OLLI, entered the DBW to be randomized 1:1 to continued baricitinib or newly started placebo (PBO) and remained until flare or up to wk32. Primary endpoint was time to flare during the DBW. Secondary endpoints included JIA-ACR30/50/70/90 response rates at wk12, and proportion of pts with a flare during the DBW. Survival curves were estimated using the Kaplan-Meier method. Results Of 220 pts enrolled, 29 participated in the PKS, 219 entered the OLLI, and 163 entered the DBW. The JIA-ACR30/50/70/90 response at wk12 was 76.3%/63.5%/46.1%/20.1%, respectively. During the DBW, time of flare was significantly shorter with PBO vs baricitinib (hazard ratio 0.24 [95% CI 0.13,0.45], p&lt;0.001; Figure 1). The proportion of pts with a flare during the DBW was significantly lower for baricitinib vs PBO (14 (17.1%) vs. 41 (50.6%), p&lt;0.001). In the PKS and OLLI periods, 126 (57.3%) pts reported ≥1 treatment emergent adverse event (TEAE), while 6 (2.7%) reported ≥1 serious adverse event (SAE); Table 1. In the DBW, 38 (46.9%) and 54 (65.9%) pts reported ≥1 TEAE for PBO and baricitinib, respectively, whereas those with ≥1 SAE were 3 (3.7%) and 4 (4.9%). The mean wks of exposure was higher in the baricitinib vs PBO group during DBW (26.34 vs 18.91) due to study design. There were no deaths, cardiovascular events or uveitis and 1 case of herpes zoster. Table 1. Safety data Events, N (% ) PKS and OLLI (N=220 ) Events, N (% ) DBW Placebo (N=81 ) DBW Baricitinib (N=82 ) Discontinuations due to AEs 2 (0.9) 2 (2.5) 1 (1.2) TEAEs 126 (57.3) 38 (46.9) 54 (65.9) most common TEAEs Nasopharyngitis 19 (8.6) URTI 1 (1.2) 9 (11.0) Headache 14 (6.4) Headache 3 (3.7) 9 (11.0) Arthralgia 12 (5.5) Nasopharyngitis 3 (3.7) 6 (7.3) URTI 11 (5.0) Arthralgia 3 (3.7) 6 (7.3) Nausea 11 (5.0) Oropharyngeal pain 1 (1.2) 5 (6.1) SAEs 6 (2.7) 3 (3.7) 4 (4.9) All reported SAEs Arthralgia 1 (0.5) COVID-19 0 1 (1.2) Joint Destruction 1 (0.5) Gastroenteritis 0 1 (1.2) Joint Effusion 1 (0.5) Headache 0 1 (1.2) JIA 1 (0.5) Pulmonary Embolism 0 1 (1.2) Musculoskeletal Chest Pain 1 (0.5) Bronchospasm 1 (1.2) 0 Decreased Appetite 1 (0.5) JIA 1 (1.2) 0 Suicide Attempt 1 (1.2) 0 Potential opportunistic infections 2 (0.9) 1 (1.2) 1 (1.2) Herpes virus 1 (0.5) Herpes virus 1 (1.2) 0 Herpes zoster 1 (0.5) Candida 0 1 (1.2) URTI= Upper Respiratory Tract Infection Conclusion Baricitinib significantly reduced time to and frequency of JIA flares in pts with JIA versus PBO, and improved JIA-ACR scores in the majority of pts within 12wks. Safety findings were consistent with the known safety profile in adult rheumatoid arthritis indications. These findings support baricitinib as a treatment for signs and symptoms of JIA with an inadequate response to cs or b-DMARDs. References [1]Giannini EH, et. al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997; 40: 1202-1209. [2]Brunner HI, et. al. Preliminary definition of disease flare in juvenile rheumatoid arthritis. J Rheumatol 2002; 29(5):1058-64. Disclosure of Interests Athimalaipet Ramanan Consultant of: Eli Lilly and Company, Abbvie, Roche, UCB, Novartis, Pfizer, and Sobi, Grant/research support from: Eli Lilly and Company, Pierre Quartier Consultant of: Eli Lilly and Company, Abbvie, Amgen, BMS, Novartis, Novimmune, Pfizer, Swedish Orphan Biovitrum, SANOFI, Speakers bureau: Abbvie, Novartis, Pfizer, Swedish Orphan Biovitrum, Nami Okamoto Consultant of: Swedish Orphan Biovitrum, Eli Lilly and Company, Speakers bureau: AbbVie, Eli Lilly and Company, Sanofi, Asahi Kasei Medical, Mitsubishi Tanabe Pharma, Bristol Myers Squibb, Pfizer Japan, Ayumi Pharma, Eisai, Torii Pharma, GlaxoSmithKline, Kyorin Pharma, Novartis, Chugai Pharmaceutical, Teijin Pharma, Gabriella Meszaros Employee of: Eli Lilly and Company, Joana Araujo Employee of: Eli Lilly and Company, Zhongkai Wang Employee of: Eli Lilly and Company, Ran Liao Employee of: Eli Lilly and Company, Brenda Crowe Employee of: Eli Lilly and Company, Xin Zhang Employee of: Eli Lilly and Company, Rodney Decker Employee of: Eli Lilly and Company, Stuart Keller Employee of: Eli Lilly and Company, Hermine Brunner Consultant of: AbbVie, Astra Zeneca-Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, Idorsia, Cerocor, Janssen, GlaxoSmithKline, F. Hoffmann-La Roche, Merck, Novartis, R-Pharm, Sanofi, Speakers bureau: Novartis, Pfizer, GlaxoSmithKline, Nicolino Ruperto Consultant of: Eli Lilly and Company, Ablynx, Amgen, Astrazeneca-Medimmune, Aurinia, Bayer, Bristol Myers and Squibb, Cambridge Healthcare Research (CHR), Celgene, Domain therapeutic, Eli-Lilly, EMD Serono, Glaxo Smith and Kline, Idorsia, Janssen, Novartis, Pfizer, Sobi, UCB, Speakers bureau: Eli Lilly and Company, Glaxo Smith and Kline, Pfizer, Sobi, UCB